Phenotypic drug discovery approaches can positively affect the translation of preclinical findings to patients. However, significant differences exist between target-based and phenotypic screening, prompting a need to re-assess our strategies and processes to most effectively prosecute phenotypic projects. First, phenotypic screens have dual goals of delivering both efficacious compound series as well as novel molecular targets for diseases of interest whereas only desirable chemical matter is sought for target screens. Second, while confirming binding and functional impact is sufficient for target screening hits, the situation is noticeably more complex for phenotypic screening hits. Here, hits acting through a number of (largely unknown) mechanisms in a large and often poorly understood biological space need to be triaged to differentiate desirable mechanisms from undesirable ones.
Given these fundamental differences, the hit triage and validation process was critically re-evaluated in light of the unique characteristics of phenotypic screening. Key considerations and specific strategies will be shared and exemplified by in house and literature case studies.

Fabien Vincent

Associate Research FellowPfizer

Fabien Vincent, Ph.D., is Associate Research Fellow in the department of Hit Discovery and Lead Profiling at Pfizer. He received a Diplome d’Ingenieur in organic chemistry from CPE Lyon (France) before conducting graduate research in the fields of chemical biology and enzymology in the laboratory of Pr. Harold Kohn at the University of Houston. He later became a post-doctoral fellow in chemical biology at the Genomics Institute of the Novartis Research Foundation in San Diego. Fabien Vincent then entered the field of drug discovery as both a research project leader and molecular pharmacology group leader. His main research interests are centered on improving the translation of pre-clinical research to patients and specifically include physiologically relevant assays, phenotypic screening and atypical molecular mechanisms of action.